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Associations between Amyloid, Cardiovascular Risk, and Cognitive Function in Korean Older Adults: Insights from the KBASE Cohort
No full textBackground:
Understanding the relationship between cardiovascular burden, amyloid, and cognition in Alzheimer’s disease (AD) is essential for targeted interventions, especially in ethnically diverse populations where research remains limited. This study aimed to investigate these relationships in a cohort of Korean older adults along the AD spectrum.
Method:
526 participants from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort were included in this study. Vascular burden was quantified using Framingham Risk Score (FRS) and participants were categorized into four groups based on combinations of FRS (FRS High or FRS Low with a median split) and amyloid status (Aβ+ or Aβ‐ based on a cut‐off of 1.2373). Cognitive function was evaluated using standardized neuropsychological tests processed with structural equation models to produce domain scores for memory, executive functioning, language, and visuospatial. ANOVA was employed at baseline to analyze cognitive differences among these groups and within each clinical diagnosis. Longitudinal mixed effects models spanning a period of four years from the initial visit captured cognitive changes over time within these groups (Figure 1).
Result:
Significant group and pairwise differences were observed among the four groups in all cognitive domains (p < 0.0001). Stratified analysis within each clinical diagnoses group revealed that CN individuals in FRS high Aβ‐ demonstrated significantly lower memory scores compared to those with FRS low Aβ‐ (p < 0.0001), this trend was absent from MCI and AD groups (Figure 2). Longitudinally, FRS high Aβ+ and FRS low Aβ+ groups consistently demonstrated lower memory scores compared to the FRS low Aβ‐ group. Interestingly, no significant difference in cognition was observed between FRS high Aβ‐ and FRS low Aβ‐ groups over time. However, the most pronounced divergence in longitudinal cognition of the four FRS and Amyloid groups was observed within the MCI diagnosis group (Figure 3).
Conclusion:
This study highlights the differential impact of cardiovascular risk on cognition depending on amyloid status and clinical diagnosis group. This underscores the importance of considering both cardiovascular risk factors and amyloid pathology early‐on in understanding clinical manifestation and cognitive decline in the AD spectrum, particularly in ethnically diverse populations
Daily Experiences of Urinary and Fecal Incontinence in Young Adults with Spina Bifida: Preliminary Results from an Ecological Momentary Assessment Study
No full textBackground: Urinary (UI) and fecal (FI) incontinence are prevalent secondary chronic conditions among young adults with spina bifida (YASB). UI and FI decrease daily functioning for YASB, but no research has prospectively examined characteristics of UI and FI among YASB. We used ecological momentary assessment (EMA) over 30 days to describe the prevalence, episode-specific characteristics and negativity associated with UI and FI among a cohort of YASB.
Method: Data were collected as part of a larger 30-day EMA study prospectively examining the daily prevalence and context of UI and FI in adults with SB. We drew an analytic sample of young adults (YASB) participants aged 18-27 years (N=23 [26.1% of all study-participants [N=88];). Participants completed an end-of-day EMA tracking the frequency, dry intervals, volume, activity avoidance, management, positive and negative mood, current UI (UIA) or FI (FIA) anxiety, past UIA and FIA and past number of UI or FI events.
Results: YASB contributed a 643 daily EMAs. Nearly 60% (370/643) of all daily entries was associated with a general report of incontinence (UI: 54.1% [348/643]; FI: 20.8% [134/643]). Prevalence, characteristics and negativity associated with UI and FI varied significantly from day-to-day. Higher UI frequency, shorter dry intervals, greater UI volume, needing management help, avoiding activities because of UI, higher past median UIA, higher negative mood and fewer past UI events were associated with higher daily UIA. Shorter FI dry intervals, higher past median FIA, higher negative mood and fewer past FI events were associated with higher daily FIA.
Discussion: Day-to-day experiences of UI and FI vary among adults with SB across multiple dimensions. Negativity about incontinence when it occurs varies not only based on individual- and episode-specific characteristics, but also on incontinence in the preceding days. Operationalizing these insights into potential clinical interventions warrants further investigation.
Discussion and implications: Young people with SB (YASB) experience day-to-day differences in the characteristics of urinary (UI) and fecal (FI) incontinence (e.g. frequency, self-management) events and the way they felt (e.g. affect) about UI and FI. The unique relationship of these factors to UI and FI anxiety suggest novel potential points of intervention
Occupational complexity and cognitive resilience in the Framingham Heart Study
No full textBackground:
Greater occupational complexity may be protective against dementia in later life, but it is unclear if it contributes to cognitive resilience and whether different aspects of occupational complexity are associated with resilience. We examined relationships between occupational complexity related to data, people, and things, and cognitive resilience to neurodegeneration.
Method:
1,699 participants from the Framingham Heart Study Offspring cohort who were aged ≥60 years, had a plasma total tau (t‐tau) measure (a marker of neurodegeneration), and a neuropsychological (NP) exam visit within five years of the plasma t‐tau measurement were included. Plasma t‐tau was measured using the Simoa assay (Quanterix) on samples collected at Exam 8 (2005‐2008). NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. Occupational data were collected at the NP exam, from which occupational complexity was disaggregated into data complexity, people complexity, and things complexity according to the 1970 US Census Dictionary of Occupational Titles. Cognitive resilience was operationalized using a residual approach by regressing each NP factor score on the plasma t‐tau measure, adjusting for age, sex, education, time from blood draw, and APOE ε4 status. The adjusted residuals were then regressed on each type of occupational complexity, dichotomized into higher complexity versus lower complexity.
Result:
The sample was, on average, 70 years of age, 53% female, and had 15 years of education. Higher data (β = 0.20, 95% confidence interval (CI) = 0.15‐0.25, p<0.001), people (β = 0.11, 95% CI = 0.07‐0.15, p<0.001), and things (β = 0.05, 95% CI = 0.01‐0.09, p = 0.015) occupational complexity were most strongly associated with resilience in executive function. Higher data (β = 0.10, 95% CI = 0.05‐0.15, p<0.001) and people (β = 0.07, 95% CI = 0.03‐0.11, p = 0.001) occupational complexity were associated with resilience in memory. Higher data (β = 0.07, 95% CI = 0.01‐0.12, p = 0.014) occupational complexity was associated with resilience in language.
Conclusion:
Specific types of occupational complexity contribute to resilience to neurodegeneration in specific cognitive domains differently. Occupational complexity may offer the most resilience in executive function and occupations with high data complexity may offer the most cognitive resilience
The role of TGFbeta signals in Lead (Pb)‐induced Cerebral Amyloid Angiopathy
No full textBackground:
Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) results in longitudinal decline in cognitive function and brain atrophy. In animals, chronic Pb exposure can increase brain Aβ deposition. However, it remains unclear how Pb induces different natures of amyloid depositions and underlying mechanisms to contribute to the pathogenesis of AD and related dementia.
Method:
Female APP/PS1 mice at 8 weeks old were administered with either 50 mg/kg Pb‐acetate (PbAc) (i.e., 27 mg Pb/kg) via oral gavage or an equivalent molar concentration of Na‐acetate (NaAc) once daily for additional 3 days or 8 weeks, in the presence or absence of an PAI‐1 inhibitor (12mg/kg). Parenchymal plaques and vascular amyloid deposition were quantitated by double staining with Thioflavin S and anti‐collagen IV antibody. Brain sections were also stained with anti‐NeuN (for neurons), anti‐myelin basic protein (for myelination) and anti‐rabbit FITC (for reactive astrocytes) antibodies. Assays for perivascular drainage as well as in vitro vascular binding with Aβ and microglial endocytosis were also performed.
Result:
2‐month Pb exposure increased vascular Aβ deposits in neocortex of female APP/PS1 mice at the 4‐month of age by almost 300% (p<0.01). In contrast, Pb only increased parenchymal amyloid in the same brain areas by 86.7% (p<0.05). Demyelination, but not neuronal loss was observed in Pb‐treated AD mice that had significantly cognitive deficits detected by Y‐maze. Following Pb treatments, the ratios of Aβ1‐40/Aβ1‐42 in Pb‐treated groups increased to 0.58 ± 0.21 in the cortical parenchyma and 0.50 ± 0.10 in the brain vasculature, as compared to those in the control group (0.39 ± 0.09 and 0.11 ± 0.02). Additionally, TGF‐β1, Smad2, PAI‐1 and fibronectin were significantly induced in cerebrovasculature isolated from mice treated with 27 mg/kg of Pb for 3 days, accompanied by dramatic inhibition of perivascular drainage and vascular binding with Aβ1‐40. Furthermore, Pb exposure induced microglial TGF‐β1 and inhibited clearance of Aβ40 and LRP‐1 expression. Interestingly enough, all of these alterations induced by Pb exposure could be markedly ameliorated by a PAI‐1 inhibitor.
Conclusion:
TGF‐β signals play distinct roles in Pb‐induced amyloid pathology
Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism
No full textNeurotensin (NTS) is a secretory peptide produced by lymphatic endothelial cells. Our previous study revealed that NTS suppressed the activity of brown adipose tissue via interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in white adipocytes upregulated food intake, while the local treatment of NTS suppressed food intake. Our mechanistic study revealed that suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2, increased the abundance of its products ceramides C20-C24, and downregulated the production of GDF15 in white adipose tissues, which was responsible for the elevation of food intake. We discovered a potential causal and positive correlation between serum C20-C24 ceramide levels and human food intake in four populations with different ages and ethnic backgrounds. Together, our study shows that NTS-NTSR2 signaling in white adipocytes can regulate food intake via its direct control of lipid metabolism and production of GDF15. The ceramides C20-C24 are key factors regulating food intake in mammals
IUSM‐Purdue TREAT‐AD Center Capabilities and Strategy to Enable and Advance Novel Therapeutic Targets for the Treatment of Alzheimer’s Disease
No full textBackground:
The TaRget Enablement to Accelerate Therapy Development of Alzheimer’s Disease (TREAT‐AD) Centers are dedicated to identifying and validating targets from the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD). The centers develop Target Enabling Packages (TEPs) to explore new therapeutic target hypotheses, moving beyond the traditional focus on amyloid or tau pathologies. In accordance with open science principles, data, methods, and tools are freely shared with the research community via an open‐access platform, the AD Knowledge Portal. The Indiana University School of Medicine and Purdue University TREAT‐AD (IUSM Purdue TREAT‐AD) Center comprises four technical cores: Bioinformatics and Computational Biology (BCB), Structural Biology and Biophysics Core (SBB), Assay Development and High Throughput Screening (ADHTS), and Medicinal Chemistry and Chemical Biology (MCCB). These cores collaborate to develop research tools that are used to validate biological targets and assess their druggability with an initial focus on understanding the role of neuroinflammation in AD.
Method:
The BCB Core supports target selection and validation with data and analysis. The SBB Core provides proteins for assay development, biophysical assays, and structural studies to aid in mode of action and Structure Activity Relationship (SAR) studies. The ADHTS Core develops in vitro and in vivo assays for SAR studies and translational PD biomarker strategies to assist in determining early phase clinical dosing regimens. The MCCB Core selects therapeutic modalities (small molecules, antibodies, siRNA) and discovers pharmacological tools, employing strategies for SAR studies to balance pharmacological and drug‐like properties.
Result:
Target Enabling Packages (TEPs) are now available via the AD Knowledge Portal for microglia targets that were prioritized for early drug discovery studies. TEPs include bioinformatics analysis, biological reagents and protocols, protein production methods, and recommended chemical probes with detailed information (Figure 1). Novel small molecule hits and leads were identified for SHIP1, PLCG2, SHP1 and LYN/HCK.
Conclusion:
A pipeline of prioritized microglia targets were selected and enabled for early drug discovery. The IUSM Purdue TREAT‐AD Center is now working with AMP‐AD researchers to explore biological hypothesis in addition to the role of neuroinflammation in AD
Cerebrovascular pathology and neurovascular coupling impairment in aged‐mouse model of Alzheimer’s disease
No full textBackground:
Vascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials. Therefore, we aim to characterize cerebrovascular amyloid angiopathy (CAA), vascular degeneration, and cerebrovascular function in an aged Tg2576 mouse model of AD.
Method:
WT and Tg2576 (∼ 2 years of age) were housed in a reversed light cycle room. Cranial window surgery and cranial window installation were performed. After 3 weeks of recovery, the animals were acclimated to an intravital multiphoton imaging platform. To visualize beta‐amyloid in the brain, Methoxy‐X04 (10mg/kg) was injected the day before the imaging. Cerebrovasculature was visualized by intravascular retro‐orbital injection of rhodamine‐dextran (5% V/W in saline). This procedure was done while the animals were under anesthesia and securely head‐fixed prior to the imaging. Z‐stack imaging was performed, and vascular structure was analyzed by using FIJI or ImageJ. Neurovascular coupling was performed to investigate vascular function in awake mice. While imaging penetrating arteriole, air‐puff stimulation of contralateral whiskers was conducted and increased vascular diameter is used as an indicator of hyperemic neurovascular function.
Result:
Investigation of cerebrovascular pathology including CAA, vascular straightness, and vascular blebbing are ongoing. During whisker stimulation, vascular diameter was relatively reduced in Tg2576 compared to WT control mice.
Conclusion:
Aged Tg2576 exhibits comorbidity of amyloid plaques, cerebral amyloid angiopathy, small vessel pathology and cerebrovascular dysfunction similar to human brain. This aged Tg2576 could be used as a preclinical translational mixed vascular/AD model
Assessing psychosocial risk factors in children with Sickle Cell Disease
No full textBackground: Individuals with Sickle Cell Disease (SCD) are a minoritized and marginalized community that have disparate health outcomes as a result of systemic racism and disease-related stigma. The purpose of this study was to determine the psychosocial risk factors for families caring for children with SCD at a pediatric SCD center through use of the Psychosocial Assessment Tool (PAT), a validated caregiver-report screener.
Methods: The PAT was administered annually during routine clinical visits and scored by the SCD Social Worker to provide tailored resources to families. The PAT stratifies scores into 3 categories of psychosocial concern: Universal, Targeted, Clinical. PATs administered between September 2021-December 2022 were analyzed.
Results: Two hundred twenty-five PATs were included for analysis. Most caregivers identified as Black, single Women over 21 years old with a high school degree or more. The average patient age was 8.2 years (0-22 years). Sixty-seven percent of PATs fell into the Universal category. Dyads that scored in the Targeted or Clinical categories were more likely to report financial hardship, caregiver mental health concerns, and family stressors (p < 0.001). Nearly 50% of all families reported some form of financial difficulty, including almost 40% in the Universal category.
Conclusions: Universal implementation of a psychosocial risk screener identified financial challenges for many families, as well as caregiver burden and mental health concerns, allowing for timely resource support. However, overall risk for many of these families was categorized as Universal or low risk, indicating that distribution of resources and support cannot be based on PAT category alone
Integrated Analysis of Single-Cell and Bulk RNA Data Reveals Complexity and Significance of the Melanoma Interactome
No full textBackground: Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms. Methods: Melanoma single-cell data were retrieved from the Broad Single Cell Portal (SCP11). High-dimensional weighted gene co-expression network analysis (hdWGCNA), CellChat, and ligand-receptor relative crosstalk (RC) scoring were employed to evaluate intercellular and intracellular signaling. The prognostic value of key regulatory genes was assessed via Kaplan-Meier (KM) survival analysis using the 'SKCM-TCGA' dataset. Results: Twenty-seven (27) gene co-expression modules were identified via hdWGCNA. Notable findings include NRAS Q61L melanomas being enriched for modules involving C19orf10 and ARF4, while BRAF V600E melanomas were enriched for modules involving ALAS1 and MYO1B. Additionally, CellChat analysis highlighted several dominant signaling pathways, namely MHC-II, CD99, and Collagen-receptor signaling, with numerous significant ligand-receptor interactions from melanocytes, including CD99-CD99 communications with cancer-associated fibroblasts, endothelial cells, NK cells, and T-cells. KM analysis revealed that higher expression of SELL, BTLA, IL2RG, PDGFA, CLDN11, ITGB3, and SPN improved overall survival, while higher FGF5 expression correlated with worse survival. Protein-protein interaction network analysis further indicated significant interconnectivity among the identified prognostic genes. Conclusions: Overall, these insights underscore critical immune interactions and potential therapeutic targets to combat melanoma resistance, paving the way for more personalized and effective treatment strategies
Peripheral metabolism informs on future cognitive decline and development of Alzheimer’s disease in population at risk
No full textBackground:
Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer’s disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g., triacylglycerol of high‐density lipoprotein). However, it is unclear if the relationship between peripheral metabolism and AD‐related markers is heterogenous among diverse populations and throughout the disease progression.
Methods:
Utilizing Alzheimer’s Disease Neuroimaging Initiative data, we determined whether baseline plasma GlycA can inform on cognitive and brain structural changes among sub‐populations with different diagnosis status. Furthermore, correlation analyses were performed between blood metabolomics and cerebrospinal fluid (CSF) proteomics data in sub‐populations with different diagnosis status or different mild cognitive impairment (MCI)/AD outcomes in 3 years.
Results:
GlycA was elevated in AD patients compared to cognitively normal participants. Baseline GlycA level was associated with executive function decline at 3‐9 year follow‐up in participants diagnosed with late mild cognitive impairment (LMCI) at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. In addition, peripheral metabolomics signatures of CSF proteomics were well‐distinguished between cognitive normal participants and AD patients. Moreover, different peripheral‐central metabolic connection was also observed in MCI‐AD converters vs. MCI‐MCI non‐converters across 3 years follow up.
Conclusion:
Peripheral inflammation was linked to future cognitive decline and brain structural atrophy for population at risk. In addition, peripheral metabolomics‐CSF proteomics correlation reveals distinguishing peripheral‐central connection patterns in AD patients as well as MCI participant soon to develop AD in 3 years. Findings here point to peripheral systemic inflammation and metabolic health in general as risk factors in AD development, pointing to therapeutic intervention related to periphery metabolic health for patients at risk